"Elimination, "Supplement required Appendix continued... Dosing Miscellaneous Metabolism" with dialysis" Anemia, anaphylactoid ACE inhibitors reactions Non-renal clearance of 2004; 5: No. 21 Benazepril R(H) 50 % NO benazeprilate Active metabolite Captopril R 25-50% YES accumulation TREATMENT OF HYPERTENSION IN DIALYSED PATIENTS Cilazapril R(H) 25 % YES István Kiss, Department of Nephrology-Hypertension, St. Imre Teaching Hospital, Csaba Farsang, 1st Department Enalapril R(H) 50 % YES Patent drug accumulation of Internal Medicine, Semmelweis University Medical Faculty, Budapest, Hungary, and Jose L. Rodicio, Department Fosinopril R and H Unchanged NO 50% hepatic elimination of Nephrology, Hospital 12 de Octubre, Madrid, Spain Lisinopril R 25 % YES Perindopril R(H) 25-50% YES Quinapril R(H) 25-50% NO Introduction medication. The reasonable target goal of a mean ambulatory blood Hypertension is common in dialysed patients (>80% at pre-dialysis pressure is less than 135/85 mmHg during the day and is less than Ramipril R(H) 25-50% YES state, >60% in patients with hemodialysis, >30 percent in those with 120/80 mmHg by night (4). Very low systolic blood pressure (<110 mm Trandolaprilate is further peritoneal dialysis) (1). The leading cause of death in dialysed patients Hg) may be associated with enhanced cardiovascular mortality (“J” or Trandolapril R(H) 50 % YES metabolized prior to excretion is cardiovascular. “U” shaped curve). An algorithm for blood pressure control is given in Angiotensin II receptor The relationship between hypertension and cardiovascular Table 2. antagonists mortality/morbidity is apparently controversial in dialysed patients because of the high prevalence of co-morbid conditions, by the under- Table 2. Algorithm for blood pressure control in dialysis patients Candesartan R (H) AVOID lying vascular pathology and by the effects of dialysis on blood pres- (modified from ref. 8) ______Eprosartan H AVOID sure. The effects of age, left ventricular hypertrophy/dysfunction (also more prevalent in patients with hypertension) and poor nutrition may 1. Estimate dry weight Irbesartan H Unchanged NO mask the true relationship between blood pressure and mortality in 2. Determine Hypertension Severity Index Losartan R (H) Unchanged NO dialysed patients (2). Hypertension has been associated with stroke, 3. Initiate non-pharmacological treatment Olmesartan R H Unchanged NO ventricular arrhythmias and progression of atherosclerosis in patients 4. Attain dry weight on hemodialysis. Improved survival due to adequate blood pressure 5. Start or increase the dose of antihypertensives to maintain BP Telmisartan H Unchanged NO control of dialysed patients has been clearly demonstrated, stressing below 150/90 mmHg Valsartan H Unchanged NO the importance of adequate antihypertensive treatment (3). 6. If BP is not controlled or dry weight not attained in 30 days, con- The etiology of hypertension in dialysis patients is multi-fac- sider: Calcium channel blockers torial (Table 1). - 24-48 hours ABPM Amlodipine H Unchanged NO - increasing time of dialysis to facilitate removal of Table 1. Etiology of hypertension in dialysed patients (from ref. 4) fluid and attainment of dry weight ______Diltiazem H Unchanged NO Risk of conduction disturbance - discontinuing sodium modelling Felodipine H Unchanged NO - sodium and volume excess due to diminished sodium excretory - increasing the dose or number of antihypertensives capacity of kidney 7. If BP remains uncontrolled, consider: Isradipine H Unchanged NO - activation of the renin-angiotensin-aldosteron system - evaluating for secondary forms of hypertension Lacidipine H Unchanged NO - increased activity of the sympathetic nervous system - peritoneal dialysis - increased endogenous vasoconstrictor (endothelin-1, Na-K- - bilateral nephrectomy (exceptional) Nicardipine H Unchanged NO ______ATPase inhibitors, adrenomedullin), and decreased vasodilator Nifedipine H Unchanged NO (nitric oxide, prostaglandins) compounds Nitrendipine H Unchanged NO - frequent administration of erythropoietin Non-pharmacological treatment of hypertension in dialysed - increased intracellular calcium content, induced by parathyroid patients (Table 3) "50-75% Active metabolites Negative inotropic and dro- Verapamil H NO hormone excess Control of plasma volume can either normalize the blood pressure or accumulation" motropic effects - calcification of arterial tree, arterial stiffness help normalize blood pressure in dialysed patients. Multiple clinical Vasodilators - pre-existent hypertension definitions of stable “dry weight” have been advanced: - nocturnal hypoxemia, frequent sleep apnea - either the blood pressure has normalized or symptoms of hyperv- Smaller doses or slow inf. To ______Diazoxide R (H) Unchanged YES avoid decreasing of BP and of olemia disappear (not merely the absence of edema); protein binding - after dialysis seated blood pressure is optimal, and symptomatic Blood pressure measurement in dialysis patients orthostatic hypotension and clinical signs of fluid overload are not Induction of lupus-like syn- Pre- or post-dialysis blood pressure measurements in patients with present; Hydralazine H (NR) Dosing interval prolonged NO drome. Prolonged activity in hemodialysis may be misleading for the diagnosis of hypertension. - at the end of dialysis patients remains normotensive until the next slow acetylators The pre-dialysis systolic blood pressure may overestimate while the dialysis without antihypertensive medication. Minoxidil H Unchanged YES Active metabolites accumulation post-dialysis systolic blood pressure may underestimate the mean Some factors may limit fluid removal by predisposing to "Accumulation of thyocyanate. inter-dialytic systolic blood pressure by 10 mmHg; the mean systolic episodes of hypotension during hemodialysis treatment, as hypoten- Nitroprusside NR Titrate by blood pressure YES Thyocyanate is dialysable" blood pressure by 7 mmHg (5). sion is one of the important cardiovascular risk factors. Limiting control The ambulatory pressure monitoring (ABPM) appears to be of volume overload in dialysis patients has been denoted as lag phe- R=renal elimination, H=hepatic elimination, NR=non-renal elimination reproducible and it has shown that blood pressure is frequently high nomenon. pre-dialysis state, it falls immediately after dialysis, and then it gradu- To avoid large inter-dialytic weight gains, patients should

References ally increases during the inter-dialytic period. ABPM may be useful in restrict salt intake (750 to 1000 mg of sodium/day). This also decreas- 1. Rahman M, Smith MC. Hypertension in hemodialysis patients. Current Hypertension Reports 10. Butt G, Winchester JF, Wilcox CS. Management of hypertension in patients receiving dialysis ther- determining “systolic blood pressure load” which is an important factor es thirst (an important factor of patient compliance). A fixed low 2001; 3: 496-502. apy. In Therapy of Nephrology and Hypertension. A companion to Brenner and Rector’s The in the development of left ventricular hypertrophy. Pre-dialysis blood dialysate sodium concentration with combination of dietary salt restric- 2. Kalantar-Zadeh K, Block G, Humphreys MH et al. Reverse epidemiology of cardiovascular risk fac- Kidney ed. by HR Brady, CS Wilcox., W.B. Saunders Company, Philadelphia, USA, 1999. tors in maintenance dialysis patients. Kidney Int 2003; 63: 793-808. 11. Jacobs C. Medical management of the dialysis patients. In Oxford Textbook of Clinical pressure correlates better with left ventricular hypertrophy than post- tion, or a programmed decrease in sodium dialysate concentration 3. Salem MM, Bower J. Hypertension int he hemodialysis population: any relation to one-year sur- Nephrology. Vol.3. Ed. By Davison AM, Cameron JS, Grünfeld J-P, Kerr DNS, Ritz E, Winearls G., dialysis blood pressure measurement (6). The dialyzed patients usu- (from 155 to 135 meq/L) may result in smaller doses of antihyperten- vival? Am J Kidney Dis 1996; 28: 737-40. Oxford Medical Publications, 1998. pp 2089-111. 4. Henrich WL, Mailloux LU. Hypertension in dialysis patients. Rose B. UpToDate online 11.3, 2004, 12. Renal Parenchymal Hypertension. Blood pressure in Chronic Dialysis Patients. In NM Kaplan: ally lose the diurnal variation in blood pressure and consequently sive drugs to control blood pressure. http://www.uptodate.com Kaplan’s Clinical Hypertension, Lipincott Williams & Wilkins, Philadelphia, USA, 2002. these patients develop nocturnal hypertension. The long, slow hemodialysis treatment (eight hours, and 5. Luik AJ, Kooman JP, Leunissen ML. Hypertension in hemodialysis patients: Is it only hyper- 13. London G, Marchais S, Guerin AP. Blood pressure control in chronic hemodialysis patients. In volaemia? Nephrol Dial Transplant 1997; 12: 1557-60. Jacobs C, Kjellstrand CM, Koch KM, Winchester JF: Replacement of renal function by dialysis, Home blood pressure measurement, an increasingly popu- three times a week) is associated with the maintenance of normoten- 6. Conion PJ, Walshe JJ, Heinle SK et al. Predialysis systolic blood pressure correlates strongly with Kluwer Academic Publishers, Dordrecht, Netherlands, 1996. pp 966-989. lar method, may be useful to estimate the blood pressure control also sion without medications in almost all patients, as this decreases affer- mean 24-hour systolic blood pressure and left ventricular mass in stable hemodialysis patients. J 14. Misra M, Reams GP, Bauer JH. Hypertension in Patients on Renal Replacement Therapy. In Am Soc Nephrol 1996; 7: 2658-63. Hypertension: A companion to Brenner and Rector’s The Kidney ed. by S Oparil, MA Weber, W.B. in dialysed patients (7). ent renal nerve activity and efferent sympathetic activation. Nocturnal 7. Agarwal R. Role of home blood pressure monitoring in hemodialysis patients. Am J Kidney Dis Saunders Company, Philadelphia, USA, 2000. hemodialysis treatment (six or seven nights a week during sleep 1999; 33: 682-7. 15. Passlick-Deetjen J, Ritz E. Management of the Renal Patient: Expert’s Recommendations and 8. Fishbane S, Maseka JK, Goreja MA et al. Hypertension in Dialysis Patients In Cardiovascular Clinical Algorithms on Cardiovascular Risk Factors. Good Nephrological Practice. ERA-EDTA. Target blood pressure of hypertensive dialysed patients hours) can also normalize blood pressure without medications in most Disease in End-stage Renal Failure. Loscalzo J, London GM. Oxford University Press, New York, Pabst Science Publishers, 2001. For most patients on dialysis (mainly in older age), the goal blood of the patients. USA, 2000. pp 471-84. 16. Locatelli F, Covic A, Chazot C, Leunissen K, Luno J, Yaqoob M. Hypertension and cardiovascular pressure is less than an average value below 150/90 mmHg on no More frequent hemodialysis treatment (two hours six times 9. Ribstein J, Mourad G, Argiles A et al. Hypertension in end-stage renal failure In Complications of risk assessment in dialysis patients. Nephrol Dial Transplant 2004; 1-11, DOI: 10.1093/ndt/gfh103 Dialysis. Ed. by Lameire N, Mehta RL. Marcel Dekker, Inc. New York, USA, 2000. pp 274-87. per week) may also be associated with normotension without medica- Pharmacological treatment of hypertension in dialyzed patients Treatment of erythropoietin-induced hypertension (9): hypotension. ACE inhibitors and ARBs decrease blood pressure, may tions and with regression of left ventricular hypertrophy. Antihypertensive drug therapy is necessary in 25-30 % of patients. - Try to decrease the actual dry weight prevent end-organ vascular diseases. Calcium channel blockers are Bilateral nephrectomy may be considered in the rare non- The type of drug or antihypertensive combination depends on severi- - decrease the dose (if possible) or interrupt treatment, and reintro- effective in reducing blood pressure but may result in severe hypoten- compliant individuals with life-threatening hypertension, whose blood ty of hypertension (Table 4) and co-morbidities. duce later at lower dosage sive episodes. Benefit from beta blockade is particularly significant in pressure cannot be controlled with any of the above detailed dialysis - introduce or increase antihypertensive medication with preference patients with type-2 diabetes mellitus and coronary heart disease. modality. Table 4. Hypertension Severity Index (HSI) of calcium channel blockers ______The clinician must define the dry weight and goal blood Treatment of hypertension in the diabetic dialysis patients: The number Conclusions pressure for each dialyzed patients based upon his or her best judg- HSI score Systolic BP (mmHg) Diastolic BP (mmHg) of dialysis patients with type-2 diabetes mellitus is rapidly increasing, The progress of dialysis technology leads to better tolerated dialysis ______ment. and these patients are generally hypertensive. Exchangeable sodium treatment and more adequate removal of sodium-water overload. Table 3. Non-pharmacological treatment of hypertension in 0 < 150 < 90 is increased in diabetic patients, and orthostatic hypotension due to Treatment of hypertension in dialysis patients still remains a careful dialysis patients 1 150-159 90-99 autonomic neuropathy, and dialysis hypotension with severe symp- clinical judgment: adequate evaluation of the dry weight, choice of ade- ______2 160-179 100-109 toms, coronary artery disease, and vascular atherosclerosis are fre- quate treatment time and frequency. In those patients in whom ultra-fil- Aerobic exercise 3 > 179 > 109 quent. Longer dialysis, slow ultrafiltration rate, hemofiltration and glu- tration and maintenance of dry weight do not adequately control hyper- ______Control of salt and fluid intake cose-containing dialysate can be used to avoid the risk of severe tension, antihypertensive medications are indicated (10-16). Cessation of smoking To calculate for an individual dialysis treatment sum the pre-dialysis Weight reduction systolic and diastolicand post-dialysis systolic and diastolic blood Appendix. Features of frequently used antihypertensive drugs in hemodialysis patients Avoidance of alcohol pressure scores. The HSI can range from 0 to 12. Long, slow and more frequent hemodialysis treatment ______"Elimination, "Supplement required Dosing Miscellaneous Metabolism" with dialysis"

Table 5 shows the compelling indications of antihypertensive drugs, and their specific side effects and special important precautions. Diuretics Thiazides/chlorthalidone R AVOID Table 5. Use of antihypertensive drugs in hemodialysis patients K+ sparing R AVOID

Drugs Compelling indication Specific side-effects Special precautions Acetazolamide R AVOID Loop agents "Left ventricular hypertrophy Anaphylactoid reactions with Ototoxicity and augment ACE inhibitors Heart failure Furosemide R (H) Useful in high doses NO AN69 dialyzator aminoglycoside toxicity Diabetes mellitus " Bumetadine R (H) Useful in high doses Dihydropyridin calcium channel Associated coronary heart blockers disease Etacrynic acid R (H) AVOID Beta-blockers Non-dihydropyridin calcium chan- Associated coronary heart Avoid combination with beta- Active metabolites nel blockers disease blockers Acebutolol H (R) 25-50% NO accumulation Avoid combination with non- Associated coronary heart Excessive bradycardia with Atenolol R 25-50% YES Removed by dialysis Beta-blockers dihydropyridin calcium channel disease liposoluble compounds blockers Bisoprolol 25 % YES

Centrally acting anti-adrenergic Post hemodialysis hypertensive Betaxolol 50 % YES None Avoid drugs rebound with methyldopa Carvedilol Unchanged NO Labetalol H Unchanged NO Alpha-adrenergic receptor "Hyperlipidemia, Beware severe hypotension blockers Insulin resistance" Metoprolol H Unchanged NO Nadolol R 50 % YES Removed by dialysis Use only in well-equipped Direct vasodilators Hypertensive crisis hospital setting Pindolol H (R) Unchanged NO Active metabolites Propranolol H Unchanged NO accumulation interfere Antihypertensive drugs dial infarction. Potential side effects include central nervous system with bilirubin dosage Calcium channel blockers are very effective and well tolerated in dial- depression (mainly lipid-soluble drugs), bradycardia, and heart failure. Class 3 antiarrhythmic Sotalol R 30 % YES ysis patients, even in those who are volume expanded. They are use- Preferable beta-blocker may be labetalol or carvedilol, which has a properties ful in patients with left ventricular hypertrophy, diastolic dysfunction and lower incidence of bronchospasm and has neutral effect on plasma Active metabolites stabile angina pectoris. Calcium channel blockers do not require sup- lipid levels. Atenolol administered three times a week post-dialysis, Tertatolol R Unchanged NO plementary post dialysis dosing. Calcium channel blockers have a may be effective. accumulation unique feature among dialysis patients since a prospective cohort Peripheral alpha-1 adrenergic receptor blocker (prazosin, Inactive metabolites Timolol H Unchanged NO study from USRDS showed a significant 26 % reduction in cardiovas- doxazosin) would help to counteract the increase in sympathetic nerve accumulation cular mortality. activity. On long-term treatment the favourably metabolic effects (on Angiotensin converting enzyme (ACE) inhibitors are effective lipids and insulin resistance) might be advantageous. These drugs are Centrally acting and well tolerated in dialysis patients. They are useful in patients with preferred in antihypertensive combinations. Interval extension of Active metabolites accumulation Methyldopa R (H) YES left ventricular hypertrophy, and in those with heart failure due to sys- Centrally acting drugs (methyldopa, clonidine, guanfacine) dose adjustment risk of prolonged hypotension tolic dysfunction. ACE inhibitors reduce mortality in hypertensive have more side effects that those described above. Newer imidazoline patients undergoing maintenance dialysis. Significantly lower mortality receptor agonists (moxonidine, rilmenidine) are felt to be safe and Clonidine R 50 % NO Risk of rebound hypertension was observed among the ACE inhibitor-treated dialysis patients (<65 effective, but only limited experience is available. Guanfacine Unchanged NO years of age). This survival benefit was independent from antihyperten- Pharmacokinetics of frequently used antihypertensive drugs sive effect. These drugs can reduce the synthesis/secretion of erythro- in dialysis patients is given in the Appendix. Beneficial effects on insulin Moxonidine, rilmenidine ? ? poietin, and trigger an anaphylactoid reaction in patients dialyzed with resistance AN69 dialyzer. Special situations Alpha-1-adrenergic blockers Angiotensin II receptor blockers (ARBs) There is only limited Treatment of refractory hypertension in hypertensive dialysis patients: experience with these drugs in end-stage renal disease. Losartan does Use of minoxidil – the strongest direct vasodilator - may be effective in Prazosin H(R) Unchanged NO First dose effect not enhance the risk of anaphylactoid dialyzator-reactions with the reducing blood pressure. Dialysed patients who are noncompliant and Beneficial effects on insulin ACE inhibitors. No dose adjustment is necessary in renal failure in the in whom volume status and hypertension cannot be adequately con- Doxazosin Unchanged NO resistance and on plasma lipids absence of volume depletion. trolled may benefit from switching to continuous ambulant peritoneal Beta-blockers are indicated in dialysis patients after myocar- dialysis (CAPD). Inactive metabolites may Urapidil H(R) Unchanged NO accumulate